Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides

Abstract

Since triglycerides (TG) are a major independent risk factor for coronary heart disease, understanding their genetic and environmental determinants is of major importance. Mouse models indicate an inverse relationship between levels of the newly identified apolipoprotein AV (APOAV) and TG concentrations. We have examined the relative influence of human APOA5 variants on plasma lipids, compared to the impact of variation in APOC3 and APOA4 which lie in the same cluster. Single nucleotide polymorphisms (SNPs) in APOA5 (S19W, -1131T>C) and APOA4 (T347S, Q360H) and an APOA4/A5 intergenic T>C SNP were examined in a large study of healthy middle-aged men (n=2808). APOA5 19WW and -1131CC men had 52% and 40% higher TG (P<0.003) compared to common allele homozygotes, respectively, effects which were independent and additive. APOA4 347SS men had 23% lower TG compared to TT men (P<0.002). Haplotype analysis was carried out to identify TG-raising alleles and included, in addition, four previously genotyped APOC3 SNPs (-2845T>G, -482C>T, 1100C>T, and 3238C>G). The major TG-raising alleles were defined by APOA5 W19 and APOC3 -482T. This suggests that the TG-lowering effect of APOA4 S347 might merely reflect the strong negative linkage disequilibrium with the common alleles of these variants. Thus variation in APOA5 is associated with differences in TGs in healthy men, independent of those previously reported for APOC3, while association between APOA4 and TG reflects linkage disequilibrium with these sites. The molecular mechanisms for these effects remain to be determined.

SNP3 polymorphism in apo A-V gene is associated with small dense LDL particles in Type 2 diabetes

“…An increase in triglyceride concentrations has been observed in heterozygote subjects for the mutated allele [1,2]. However, another study found no significant increase in triglycerides in heterozygote subjects, but found one among homozygotes for the mutated allele [3]. In our group, we found no significant differences in triglyceride concentrations.…”

“…Its frequency is 12% in Afro-Americans, 16% in Hispanics, 6 to 16% in Caucasians and 7% in a Spanish control cohort [1,2,3,4]. The heterozygote subjects for rare SNP3 allele (C/T) are related to an increase in triglycerides in Hispanic and Caucasian men, although these data were not observed in another study where the increase in triglycerides was only statistically significant in homozygotes for the mutated allele [3]. Hypertriglyceridaemia is the main factor in determining the size of the LDL.…”

The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits

“…The variants selected were the apolipoprotein A-V (APOA5) single nucleotide polymorphisms (SNPs) rs662799 and rs3135506; the lipoprotein lipase (LPL) SNP rs328; and the glucokinase (GCK) SNP rs1799884, which have been shown in multiple cross-sectional studies to be associated with triacylglycerol (APOA5 and LPL) [16][17][18][19][20][21], HDL-C (LPL) [20,21] and fasting glucose (GCK) [9,22] levels, traits important in the risk of diabetes and cardiovascular disease.…”

Plasma apolipoprotein A5 and triglycerides in type 2 diabetes

“…Human studies have focused upon the association between genetic variation in the APOA5 gene and plasma triglyceride levels. Two common APOA5 polymorphisms, the −1131T→C polymorphism and the c56C→G (S19W) polymorphism in the APOA5 signal peptide, are of particular interest [12,13]. The rare alleles of each polymorphism both show a positive association with elevated plasma triglyceride levels in clinical studies as well as in the general population.…”